Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab

Abstract

Objectives Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs. Methods We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours. Results We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis. Conclusions As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.

Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment

“…The fact that our 10 cases occurred only after anti-PD-1 and not anti-CTLA-4 antibody treatment (except one patient who received both during four cycles) suggests a contrast between the IrAE occurring after blockade with CTLA-4 (colitis, endocrine disorders, skin rashes) and PD-1/PDL1 like non-specific arthritis, sicca syndrome11 RA, PMR (this report) and connective tissue diseases 19…”

Unerwünschte Wirkungen der Immuntherapie

“…Im Gegensatz dazu sind die Toxizitäten von Nivolumab und Pembrolizumab dosisunabhängig und mit höheren Raten von hepatologischen und pulmonalen Nebenwirkungen assoziiert [19,26]. Der Beginn immunbedingter Nebenwirkungen nach Therapiestart von Ipilimumab zeigt eine zeitliche Assoziation [19] Manche Patienten weisen simultan mehre als eine Nebenwirkung auf [7].…”

“…Die manifeste Arthritis ist weniger häufig (Prävalenz ca. 2 % unter Anti-PD-1-Inhibitoren [26,27] [7,8]). In der PET-CT zeigt sich eine erhöhte FDG-Aufnahme in der Synovia multipler bilateraler Gelenke bei Arthritis und bei Myositis in Muskeln (.…”

“…6; [6,20]). Eine Differenzierung zur rheumatoiden Arthritis kann sehr schwierig sein, antizyklische Citrullinated-peptid-Antikörper und Rheumafaktoren werden jedoch für gewöhnlich nicht gefunden [7]. Suarez-Almazor et al [27] …”

Nivolumab induced remitting seronegative symmetrical synovitis with pitting edema in a patient with melanoma: a case report

“…Other checkpoint inhibitors, such as ipilimumab, target cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). As a byproduct of immune activation, a spectrum of immune-related adverse effects including vitiligo, Sweet's syndrome, mucositis, lymphocytic rash, non-infectious colitis, pneumonitis, hypophysitis, autoimmune thyroid disease, type 1 diabetes, Guillain-Barré syndrome, fulminant myocarditis, inflammatory arthritis, sicca syndrome, and uveitis have been extensively reported [1][2][3][4][5][6][7][8][9][10][11][12].…”